Nanoparticle-mediated Intracellular Delivery of Imatinib Mesylate(STI571) Ex Vivo Suppresses Vein Grail Neointima Formation

• Project/Area Number: 18591555
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Thoracic surgery
• Research Institution: Kyushu University
• Principal Investigator: SHIOSE Akira Kyushu University, Faculty of Medical Sciences, Co Researcher (30363336)
• Co-Investigator(Kenkyū-buntansha): MASUDA Munetaka Yokohama City University, 外科治療学, Professor (10190365) ; TOMITA Yukihiro Kyushu University, Hcepital, Associate Professor (90180174) ; KAWASHIMA Yoshiaki Aichi Gakuin University, School of Pharmacy, Professor (30082978) ; EGASHIRA Kensuke Kyushu University, Faculty of Medical Sciences, Associate Professor (60260379) ; TOMINAGA Ryuji Kyushu University, Faculty of Medical Sciences, Professor (70136464)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: vein graft disease / nanotechnology / ドラッグ・デリバリー・システム / ナノテクノロジー / 静脈グラフト

Research Abstract

Background: Clinical outcome of revascularization using autologous vein graft is limited by vein graft neointima formation. Platelet-derived growth factor (PDGF), expressed by vascular smooth muscle cells (VSMCs) plays a central role in the pathogenesis of neointima formation. Therefore, optimal nanotechnology-based drug delivery system (Nano-DDS) of PDGF receptor tyrosine kinase (TK) inhibitor, imatinib mesylate (STI571) can be an innovative strategy for clinical application. Methods and Results: We have developed Nano-DDS using PLGA nanoparticles (NPs) for local delivery. STI571 NP prevented PDGF-induced phosphorylation of PDGF receptor TK and normalized the PDGF-induced proliferation and migration. Incubation of excised rabbit jugular vein ex vivo with FITC NP for 30 min resulted in highly efficient intracellular delivery rate (> 99 %). The excised jugular vein was treated ex vivo with PBS, STI571 only, FITC NP only. or STI571 NP for 30 min, and then interposed into the carotid artery position. FITC-positive cells were detected in the neointima and media (12 ア 5 %) 28 days after FITC NP treatment. STI571 NP markedly suppressed neointima formation 28 days after grafting compared with other groups. STI571 NP also inhibited the appearance of proliferating cells and increased phosphorylation of PDGF receptor TK, but did not affect endothelial regeneration process. Conclusions: Nano-DDS of STI571 may be a clinically promising therapeutic strategy for prevention of vein graft failure.

Research Products

• [Journal Article] Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein neointimal formation (2007)
  • Author(s): Tatewaki H, Egashira K, Kimura S, Nishida T, Morita S, Tominaga R
  • Journal Title: Journal of Vascular Surgery 45 Pages: 1236-1243
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Blockade of monocyte chemoattractant protein-1 by adenoviral gene transfer inhibits experimental vein neointimal formation (2007)
  • Author(s): Tatewaki, H, Egashira, K, Kimura, S, Nishida, T, Morita, S, Tominaga, R
  • Journal Title: Journal of Vascular Surgery 45 Pages: 1236-1243
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Blockade of Monocyte Chemoattractant Protein-1 by Adenoviral Gene Transfer Inhibits Experimental Vein Graft Neointimal Formation. (2007)
  • Author(s): Takewaki H, Egashira K, Kimura S, Nishida T, Morita S, Tominaga R
  • Journal Title: Journal of Vascular Surgery in press